This K24 application addresses urgent public health needs to develop a pipeline of young scientists pursuing translational research on neurologic disorders, and to develop a better understanding of pathogenic mechanisms and phenotypes in familial Alzheimer's disease (FAD). The dual goals of this proposal are: (1) to establish an innovative interdisciplinary mentoring program focused on enhancing the research training and career development of fellows and early-stage junior faculty in the Department of Neurology at the Massachusetts General Hospital (MGH); and (2) to expand the patient-oriented component of the PI's translational research on AD through the acquisition of new approaches involving generation and multidisciplinary analysis of induced pluripotent stem cell-derived neurons bearing human FAD patient-specific PSEN1 mutations. The K24 award will be critical in allowing the PI to realize these goals by providing protected time from growing clinical and administrative burdens. The proposed mentoring program, which builds on the PI's substantial experience as a clinician-scientist and mentor, emphasizes interdisciplinary education, training, and mentoring in translational neuroscience. The program is based on the PI's assessment of the needs of junior researchers and the conviction that the complexity of brain disorders will increasingly require interdisciplinary approaches that take advantage of advances in basic neuroscience, genetics and genomics, and stem cell technologies. The mentoring program benefits from the strengths of the MGH Neurology Department and collaborative alliances with other highly relevant departments and centers at MGH, Harvard, and MIT. Specific components include an interdisciplinary network of faculty mentors; state-of-the-art courses on genetics, genomics and cellular reprogramming technologies; workshops to enhance grant-writing skills; a seminar series for informal presentation of research ideas and results by fellows and junior faculty; and incorporation of Ph.D. scientists into inpatient clinical teams. Success of these mentoring efforts will be tracked by specific metrics including grant submission and success rates, attendance at workshops, courses, and seminars, and internal surveys. The proposed research program builds on the PI's extensive experience in mechanistic studies of FAD in cell culture and mouse models systems, and seeks to translate intriguing recent findings from the PI's generation and analysis of novel Presenilin-1 knock-in mice to human FAD patients. To accomplish these aims, the PI will acquire new expertise in generation and functional genomic analysis of human iPSC-derived neurons, which he will apply to analysis of multiple FAD-relevant phenotypes. Acquisition and implementation of these techniques will be facilitated by a team of expert collaborators. These studies have the potential to provide new insights into pathogenic mechanisms in FAD, potentially revealing novel target pathways and avenues for therapeutic development.